title: B Cell and BAFF dependence of IFN-α-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice.
abstract: IFN-α is a potent activator of innate and adaptive immunity, and its administration to preautoimmune (NZB×NZW)F1 mice promotes virulent systemic lupus erythematosus (SLE) disease. Given the known contributions of B cells and BAFF to SLE, we evaluated the ability of IFN-α administration to induce disease in wild-type (WT), B cell-deficient, and BAFF-deficient NZM 2328 mice. Whereas WT mice rapidly developed proliferative glomerulonephritis, marked proteinuria, and increased mortality in response to IFN-α administration, B cell-deficient mice developed neither renal pathology nor clinical disease. Moreover, BAFF-deficient mice, despite developing limited glomerular IgG and C3 deposition, also remained free of histological glomerulonephritis and clinical disease. Strikingly, similar T cell expansion and serum IgG responses were observed in adenovirus (Adv)-IFN-treated WT and BAFF-deficient mice despite their disparate pathological and clinical responses, whereas numbers of activated B cells increased in WT mice but not in BAFF-deficient mice. Nonetheless, B cell, plasma cell, and T cell infiltration of the kidneys in Adv-IFN-treated WT mice was similar to that in WT mice treated with Adv-control. Its ability to promote SLE disease in WT mice notwithstanding, IFN-α administration failed to drive the preferential expansion of CD4(+) memory T cells that occurs during the natural course of disease, and glomerular infiltration of macrophages failed to associate with development of disease. These results collectively suggest that therapeutic targeting in SLE of BAFF and/or B cells in SLE could be successful even in states of IFN-α overexpression. Moreover, our results document important biological differences between IFN-α-driven and spontaneous natural SLE disease.
authors.affiliation: Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Noam
authors.initials: N
authors.lastname: Jacob
authors.forename: Shunhua
authors.initials: S
authors.lastname: Guo
authors.forename: Alexis
authors.initials: A
authors.lastname: Mathian
authors.forename: Michael N
authors.initials: MN
authors.lastname: Koss
authors.forename: Simona
authors.initials: S
authors.lastname: Gindea
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.forename: William
authors.initials: W
authors.lastname: Stohl
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007074:Immunoglobulin G; D016898:Interferon-alpha; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C505720:Tnfsf13b protein, mouse